The present invention relates to methods of treating neuropathic pain with heteroarylmethanesulfonamides.
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Chronic or intractable pain, as may occur in conditions such as bone degenerative diseases, AIDS, Reflex sympathetic dystrophy (RSD), and cancer, is a debilitating condition which is treated with a variety of analgesic agents, and often opioid compounds, such as morphine. This type of pain is classified as nociceptive and is experienced in response to potentially tissue-damaging thermal, mechanical or chemical energy impinging upon specialized nerve endings of A and C fibers. Thus pain is usually perceived in response to nociceptive signaling by the nervous system as a result of noxious stimuli.
A few examples of neuropathic pain syndromes without nociception, i.e., not in response to noxious external stimuli are: diabetic neuropathy; postparapalegia pain; postherpetic neuralgia; reflex sympathetic dystrophy; thalamic syndrome; nerve root avulsion pain; phantom limb pain; postthoracotomy pain; tic douloureux and arachnoiditis.
Neuropathic pain, then, is a particular type of pain that has a complex and variable etiology. It is frequently a chronic condition attributable to complete or partial transection of a nerve, trauma or injury to a nerve, nerve plexus or soft tissue, or other conditions, also including cancer, AIDS and idiopathic causes. Neuropathic pain is characterized by hyperalgesia (lowered pain threshold and enhanced pain perception) and/or by allodynia (pain from innocuous mechanical or thermal stimuli). The condition is progressive in nature. The hyperesthetic component of neuropathic pain does not respond to the same pharmaceutical interventions as do the more usual nociceptive forms of pain, and development of effective long-term treatment modalities has been problematic. Repeated C fiber stimulation results in increased spinal afferent processing which is probably related to the hyperalgesia and allodynia symptoms. Evidence points to a complex scenario in which continued C fiber stimulation leads to local spinal release of glutamate, which activates spinal N-methyl-D-aspartate receptors. This activation then leads to increased intracellular Ca and later to spinal formation of several intermediaries, including prostanoids and nitric oxide. Both intermediaries facilitate spinal processing of signals directly by increasing the release of spinal neurotransmitters, and lead to the facilitated state of hyper-responsive pain signaling that lacks true nociceptive stimulus.
Opioid compounds (opiates) such as morphine, while effective in producing analgesia for many types of nociceptive pain, are generally not effective for treating the progressive stages of neuropathic pain. Moreover, if somewhat effective, these compounds are known to induce tolerance in patients, so that increased doses are required to achieve a satisfactory analgesic effect. At high doses, these compounds produce side effects (such as respiratory depression) which can be life threatening. In addition, opioids can produce physical dependence in patients.
Calcium blocking agents, including a number of L-type calcium channel antagonists, were tested as adjunct therapy to morphine analgesia, and positive results were attributed to their direct effects on calcium availability, since calcium itself is known to attenuate the analgesic effects of certain opioid compounds (Ben-Sreti, et al., 1983). EGTA, a calcium chelating agent, is effective in increasing the analgesic effects of opioids. However, results from tests of calcium antagonists as adjunct therapy to other opioids have been contradictory; some L-type calcium channel antagonists have been shown to increase the analgesic effects of opioids, while others of these compounds have been shown to decrease opioid effects (Contreras, et al., 1988).
U.S. Pat. No. 5,364,842 and 5,587,454 describe the effectiveness of N-type calcium channel blocking omega-conopeptide compositions in certain animal models of pain, including neuropathic pain. However, these compounds, being peptides, are not easily administered orally, but rather may be administered into the cerebrospinal fluid or other areas of the spinal column. By contrast, zonisamide is a T- and L-type calcium channel blocker and tests in animals (see Examples) have shown oral activity.
The anticonvulsant agent gabapentin exhibits anti-hyperalgesic properties in animal models of neuropathic pain. Diabetic rats display increased nocifensive behavior (i.e. avoidance behavior of stimuli) during the formalin test of persistent chemical irritation to the paw, suggesting the presence of abnormal pain processing mechanisms. In a study based on formalin-evoked behavior in diabetic rats, they were shown to have increased flinching during the normally quiescent phase of the 5.0% formalin test. Gabapentin (50 mg/kg i.p. 30 min pre-test) suppressed flinching during phases 1 and 2 of the formalin test in both control and diabetic rats. The findings were interpreted as showing efficacy of gabapentin against abnormal sensory processing in diabetic rats and the possible benefit for treating painful diabetic neuropathy. Since gabapenitin is an approved drug for use in humans in epilepsy, it has also be used in treatment of neuropathic pain, but the rather high dosages required to obtain a therapeutic effect make it undesireable for treatment of certain segments (e.g. the elderly) of the patient population.
Gabapentin (1-(aminomethyl)cyclohexaneacetic acid) is structurally related to the neurotransmitter GABA (gamma-aminobutyric acid) but it does not interact with GABA receptors, nor is it converted metabolically into GABA or a GABA agonist, nor is it an inhibitor of GABA uptake or degradation. Gabapentin was tested in radioligand binding assays at concentrations up to 100 xcexcM and did not exhibit affinity for a number of other common receptor sites, including benzodiazepine, glutamate, N-methyl-D-aspartate (NMDA), quisqualate, kainate, strychnine-insensitive or strychnine-sensitive glycine, alpha1, alpha2, or beta adrenergic, adenosine A1 or A2, cholinergic, muscarinic or nicotinic, dopamine D1 or D2, histamine H1, serotonin S1 or S2, opiate mu, delta or kappa, voltage-sensitive calcium channel sites labeled with nitrendipine or diltiazem, or at voltage-sensitive sodium channel sites with batrachotoxinin A 20-alpha-benzoate (excerpt from Physicians Desk Reference (1999 PDR Supplement B) Edition monograph for Neurontin Capsules). In vitro studies with radiolabeled gabapentin have revealed a gabapentin binding site in areas of rat brain including neocortex and hippocampus. although the identity and function of this binding site remain to be elucidated.
The heteroaryl methanesulfonamides of the invention are described in U.S. Pat. No. 4,172,896, which is hereby incorporated herein by reference. The active compounds of the invention are described by the generic structure of formula I 
wherein R is hydrogen or a halogen atom, R2 and R3 are the same or different and are each hydrogen or a straight or branched alkyl having 1 to 3 carbon atoms, and one of X and Y is a carbon atom and another is a nitrogen atoms, provided that the methanesulonamido group is bonded to the carbon atom of either X and Y.
Compounds of the formula have a biochemical profile that includes inhibition of GABA release, sodium channel blockade, blockade of L- and T-type calcium channels and free-radical scavenger activity. The compounds are best characterized in vivo as anti-convulsants, and the compound given the generic name, zonisamide is used in the treatment of epilepsy in humans. Zonisamide has the chemical structure of 1,2-benzisoxazole-3-methanesulfonamide. Additionally, zonisamide is further described in the Merck Index (11th Ed.) at monograph no. 10094. It is the unexpected finding of the present invention that compounds of formula I reduce the severity of neuropathic pain in mammals.
The invention relates to methods for the treatment of neuropathic pain in mammals which comprises administering to a mammal in need of such treatment an efficacious amount of a compound of formula I 
wherein R is hydrogen or a halogen atom, R2 and R3 are the same or different and are each hydrogen or a straight or branched alkyl having 1 to 3 carbon atoms, and one of X and Y is a carbon atom and another is a nitrogen atoms, provided that the methanesulonamido group is bonded to the carbon atom of either X and Y.
A halogen atom is defined as fluorine, chlorine, bromine or iodine. Alkyl is defined as a straight or branched chain of carbon atoms connected by single bonds. Other terms in the description not defined herein have the standard meaning ascribed to them by one of skill in the relevant art.
Preferably the compound is 1,2-benzisoxazole-3-methanesulfonamide (zonisamide).
The compound may be administered in the range of 1 mg/kg to 400 mg/kg per day through a variety of routes of administration, including oral, topical, rectal, injection, or implantation. A preferred route of administration is via oral dosing.
The compounds of formula I may be used in treating a variety of neuropathic disorders, including: diabetic neuropathy, neuropathy secondary to nerve trauma, trigeminal neuralgia, post herpetic neuralgia, reflex sympathetic dystrophy, cancer pain and AIDS-related neuropathy.
These and other objects and features of the invention will become more fully apparent when the following detailed description of the invention is read in conjunction with the accompanying drawings.